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A Study to Determine the Effects of Food and Multiple Dosing on the Pharmacokinetics of Vorinostat Given Orally to Patients with Advanced Cancer

Authors' Affiliations: ¹ The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey and ² Merck Research Laboratories, Merck & Co., Whitehouse Station, New Jersey

Requests for reprints: Eric H. Rubin, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903-2681. Phone: 732-235-6777; Fax: 732-235-7735; E-mail: ehrubin{at}umdnj.edu.

Purpose: This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics.

Experimental Design: Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose.

Results: The apparent t_1/2 of vorinostat was short (1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and T_max was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting.

Conclusions: Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.

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